DE10260618A1 - Tumor-inhibiting fused azepinone derivatives - Google Patents
Tumor-inhibiting fused azepinone derivatives Download PDFInfo
- Publication number
- DE10260618A1 DE10260618A1 DE10260618A DE10260618A DE10260618A1 DE 10260618 A1 DE10260618 A1 DE 10260618A1 DE 10260618 A DE10260618 A DE 10260618A DE 10260618 A DE10260618 A DE 10260618A DE 10260618 A1 DE10260618 A1 DE 10260618A1
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- Prior art keywords
- compound
- hydrogen
- general formula
- halogen
- complex
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- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 9
- DXZDEAJXVCLRLE-UHFFFAOYSA-N azepin-2-one Chemical class O=C1C=CC=CC=N1 DXZDEAJXVCLRLE-UHFFFAOYSA-N 0.000 title abstract description 10
- 230000002401 inhibitory effect Effects 0.000 title description 2
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 5
- 238000011282 treatment Methods 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 18
- -1 cyano, formyl Chemical group 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
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- 125000001424 substituent group Chemical group 0.000 claims description 6
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- VDTXDALRBZEUFV-UHFFFAOYSA-N 3,4-dihydro-1h-1-benzazepine-2,5-dione Chemical compound N1C(=O)CCC(=O)C2=CC=CC=C21 VDTXDALRBZEUFV-UHFFFAOYSA-N 0.000 description 2
- ZKQWCEXMWMUQBA-UHFFFAOYSA-N 9-bromo-6-methylsulfanyl-7,12-dihydroindolo[3,2-d][1]benzazepine Chemical compound C1C(SC)=NC2=CC=CC=C2C2=C1C1=CC(Br)=CC=C1N2 ZKQWCEXMWMUQBA-UHFFFAOYSA-N 0.000 description 2
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- 230000000259 anti-tumor effect Effects 0.000 description 1
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- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
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- 239000011230 binding agent Substances 0.000 description 1
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- 239000001506 calcium phosphate Substances 0.000 description 1
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- 238000002512 chemotherapy Methods 0.000 description 1
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- 238000000576 coating method Methods 0.000 description 1
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- 239000007903 gelatin capsule Substances 0.000 description 1
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- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 1
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- 238000001802 infusion Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000009701 normal cell proliferation Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- BTIHMVBBUGXLCJ-OAHLLOKOSA-N seliciclib Chemical compound C=12N=CN(C(C)C)C2=NC(N[C@@H](CO)CC)=NC=1NCC1=CC=CC=C1 BTIHMVBBUGXLCJ-OAHLLOKOSA-N 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
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- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
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- 239000002700 tablet coating Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Die vorliegende Erfindung betrifft annellierte Azepinonderivate, ein Verfahren zu deren Herstellung, Metallkomplexe der annellierten Azepinonderivate, sowie deren Verwendung zur Behandlung von Tumorerkrankungen.The present invention relates to fused azepinone derivatives, a process for their preparation, metal complexes of fused azepinone derivatives, and their use for the treatment of tumor diseases.
Description
Die vorliegende Erfindung betrifft annellierte Azepinonderivate, ein Verfahren zu deren Herstellung, Metallkomplexe der annellierten Azepinonderivate, sowie deren Verwendung zur Behandlung von Tumorerkrankungen.The present invention relates to Annellated azepinone derivatives, a process for their preparation, metal complexes the fused azepinone derivatives and their use for treatment of tumor diseases.
Die genaue und stufenweise Abfolge der einzelnen Schritte des Zellzyklus ist ein essentieller Bestandteil der normalen Zellproliferation. Für die Überleitung der einzelnen Stufen ineinander sind in erster Linie die verschiedenen Formen der Cyclin abhängigen Kinasen (CDKs) verantwortlich. In vielen menschlichen Tumoren kann eine Deregulierung der Aktivität von Cyclin abhängigen Kinasen beobachtet werden. Diese beruhen entweder auf der Überexpression von Cyclinen oder aber auf dem Fehlen entsprechender natürlicher Inhibitoren durch genetische Veränderungen. Daher stellen CDKs eine attraktive Klasse an Targets für die chemotherapeutische Bekämpfung von Tumorerkrankungen dar. Es gibt allerdings bis jetzt nur wenige Substanzen, die in der Lage sind, als selektive CDK-Inhibitoren zu wirken, wobei besonders Flavopiridol, Roscovitine und die Purvalanole als wichtige Verbindungen bzw. Verbindungsklassen zu nennen sind.The exact and gradual sequence the individual steps of the cell cycle is an essential component normal cell proliferation. For the transition of the individual stages intertwined are primarily the different forms of cyclin dependent Kinases (CDKs) responsible. In many human tumors a deregulation of activity dependent on cyclin Kinases are observed. These are based either on overexpression of cyclins or on the lack of corresponding natural ones Inhibitors due to genetic changes. Therefore, CDKs represent an attractive class of targets for chemotherapy fight of tumor diseases. However, there are only a few so far Substances that are able to act as selective CDK inhibitors to act, especially Flavopiridol, Roscovitine and the Purvalanole are to be mentioned as important connections or connection classes.
Annellierte Azepinone stellen eine weitere bedeutende Klasse von CDK-Inhibitoren dar. Der Grundkörper dieser Verbindungsklasse erlaubt eine Reihe von Modifikationen zur Strukturoptimierung mit Blick auf die biologische Wirksamkeit. Besonders die Klasse der Indolo[3,2-d]benzazepinone ist eine Verbindungsklasse, deren Potential als CDK-Inhibitoren zur Zeit intensiv untersucht wirdAnnellated azepinones represent one represents another important class of CDK inhibitors. The basic body of these Connection class allows a number of modifications to optimize the structure with a view to biological effectiveness. Especially the class the indolo [3,2-d] benzazepinone is a class of compounds whose Potential as CDK inhibitors is currently being intensively investigated
So werden in der WO 99/65910 substituierte Azepinone als Inhibitoren der Cyclin abhängigen Kinasen beschrieben. Auch in der WO 01/60374 ist die Verwendung von geeignet substituierten Azepinonderivaten zur Herstellung von Medikamenten, die Inhibitoren für GSK-3β, CDK1 oder CDK5 enthalten, offenbart. Sowohl in der WO 99/65910 als auch in der WO 01/60374 wurde das Substitutionsmuster an den beiden Arylringen des tetracyclischen Grundkörpers der entsprechenden Azepinonderivate variiert.So are substituted in WO 99/65910 Azepinones are described as inhibitors of cyclin-dependent kinases. WO 01/60374 also uses suitably substituted ones Azepinone derivatives used in the manufacture of drugs that are inhibitors for GSK-3β, CDK1 or CDK5 included. Both in WO 99/65910 and in WO 01/60374, the substitution pattern on the two aryl rings of the tetracyclic body of the corresponding azepinone derivatives varies.
Ein Austausch der Lactamcarbonylgruppe im Azepinonring gegen eine Thioimidat- oder eine Hydroxyimidat-Gruppierung ergab keine Verbesserung in der biologischen Wirksamkeit (Schultz et al. J. Med. Chem. 1999, 42, 2909-2919).An exchange of the lactam carbonyl group in the azepinone ring against a thioimidate or a hydroxyimidate group showed no improvement in biological effectiveness (Schultz et al. J. Med. Chem. 1999, 42, 2909-2919).
Aufgabe der vorliegenden Erfindung ist es, Verbindungen zur Behandlung von Krebserkrankungen zur Verfügung zu stellen, die eine hohe Wirksamkeit aufweisen.Object of the present invention is compounds available to treat cancer places that are highly effective.
Die Aufgabe wird gelöst durch
eine Verbindung der allgemeinen Formel (I) oder (II) wobei
X ausgewählt ist
aus den folgenden Gruppen (a), (b) und (c) qworin
R1,
R2 und R11-R15 unabhängig
voneinander ausgewählt
sind aus der Gruppe bestehend aus Wasserstoff, Halogen, Hydroxyl
und substituiertem oder unsubstituiertem Alkyl, Alkenyl, Alkinyl,
Cycloalkyl, Cycloalkenyl und Aryl, und
R3-R10 und R1
6-R20 unabhängig voneinander
ausgewählt
sind aus der Gruppe bestehend aus Wasserstoff, Amino, Nitro, Cyano,
Formyl, Carboxyl, SO3H, Hydroxy, Halogen
und substituiertem oder unsubstituiertem Alkyl, Alkenyl, Alkinyl,
Cycloalkyl, Cycloalkenyl, Aryl, Alkoxy, Alkylmercapto, Dialkylamino,
und
physiologisch verträgliche
Additionssalze davon.The object is achieved by a compound of the general formula (I) or (II) in which
X is selected from the following groups (a), (b) and (c) qworin
R 1 , R 2 and R 11 -R 15 are independently selected from the group consisting of hydrogen, halogen, hydroxyl and substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and aryl, and
R 3 -R 10 and R 1 6 -R 20 are independently selected from the group consisting of hydrogen, ami no, nitro, cyano, formyl, carboxyl, SO 3 H, hydroxy, halogen and substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, alkoxy, alkylmercapto, dialkylamino, and
physiologically acceptable addition salts thereof.
Weiterhin wird die Aufgabe der vorliegenden
Erfindung gelöst
durch einen Komplex der allgemeinen Formel (III),
R1 und R2 wie vorstehend
definiert sind,
R3-R10 und
R16-R20 wie vorstehend
definiert sind,
Y ein physiologisch verträgliches Anion ist, und
M
Ga, Fe, Ru oder La ist, i 0, 1 oder 2 ist;
n 1 oder 2 ist,
und
physiologisch verträgliche
Additionssalze davon.Furthermore, the object of the present invention is achieved by a complex of the general formula (III)
R 1 and R 2 are as defined above,
R 3 -R 10 and R 16 -R 20 are as defined above,
Y is a physiologically acceptable anion, and
M is Ga, Fe, Ru or La, i is 0, 1 or 2;
n is 1 or 2,
and physiologically acceptable addition salts thereof.
Weiterhin betrifft die vorliegende
Erfindung ein Verfahren zur Herstellung eines Komplexes der allgemeinen
Formel (III)
R1-R10 und R16-R20 wie oben definiert
sind,
i 0, 1 oder 2 ist,
n 1 oder 2 ist
mit einer
Verbindung der allgemeinen Formel (V) umgesetzt wird,
M
und Y wie oben definiert sind und m 1, 2 oder 3 ist.The present invention further relates to a process for the preparation of a complex of the general formula (III)
R 1 -R 10 and R 16 -R 20 are as defined above,
i is 0, 1 or 2,
n is 1 or 2
is reacted with a compound of the general formula (V),
M and Y are as defined above and m is 1, 2 or 3.
Vorzugsweise ist m 3, wenn Y ein einwertiges Anion ist.Preferably m is 3 when Y is monovalent anion is.
Falls die Gruppen R1-R20 substituiert sind, sind die Substituenten bevorzugt Halogen, Hydroxyl, Alkyl, Alkoxy, Alkoxycarbonyl, Alkylmercapto, Dialkylamino, Dialkylaminocarbonyl und/oder Nitril und es sind vorzugsweise 1 bis 3 Substituenten, insbesondere 1 Substituent anwesend.If the groups R 1 -R 20 are substituted, the substituents are preferably halogen, hydroxyl, alkyl, alkoxy, alkoxycarbonyl, alkylmercapto, dialkylamino, dialkylaminocarbonyl and / or nitrile and there are preferably 1 to 3 substituents, in particular 1 substituent.
Ferner sind substituierte Gruppen R3-R10 und R16-R20 bevorzugt unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogenalkyl, Hydroxyalkyl, Alkoxy, Alkoxyalkylen, Alkoxycarbonyl, Alkoxycarbonylalkylen, Alkylmercapto, Alkylmercaptoalkylen, Dialkylamino, Dialkylaminoalkylen, Dialkylaminocarbonyl, Dialkylaminocarbonylalkylen und Alkylnitril.Furthermore, substituted groups R 3 -R 10 and R 16 -R 20 are preferably selected independently of one another from the group consisting of haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkylene, alkoxycarbonyl, alkoxycarbonylalkylene, alkylmercapto, alkylmercaptoalkylene, dialkylamino, dialkylaminoalkylene, dialkylaminocarbonyl, dialkylaminocarbonylalkylene and dialkylaminocarbonylalkylene.
Weiterhin beinhalten Alkyl in den Substituenten R1-R20 vorzugsweise 1 bis 10, stärker bevorzugt 1 bis 6 und insbesondere 1 bis 3 Kohlenstoffatome, Alkenyl oder Alkinyl vorzugsweise 2 bis 10, stärker bevorzugt 2 bis 6 und insbesondere 2 bis 3 Kohlenstoffatome, Cycloalkyl oder Cycloalkenyl, vorzugsweise 3 bis 10, stärker bevorzugt 3 bis 8 und insbesondere 3 bis 6 Kohlenstoffatome und Aryl vorzugsweise 6 bis 14, stärker bevorzugt 6 bis 10 und insbesondere 6 Kohlenstoftatome.Furthermore, alkyl in the substituents R 1 -R 20 preferably contain 1 to 10, more preferably 1 to 6 and in particular 1 to 3 carbon atoms, alkenyl or alkynyl preferably 2 to 10, more preferably 2 to 6 and in particular 2 to 3 carbon atoms, cycloalkyl or Cycloalkenyl, preferably 3 to 10, more preferably 3 to 8 and especially 3 to 6 carbon atoms and aryl preferably 6 to 14, more preferably 6 to 10 and especially 6 carbon atoms.
Weiterhin sind bevorzugt R1, R2 und R11-R15 unabhängig voneinander
ausgewählt
aus der Gruppe bestehend aus Wasserstoff, C1-C6-Alkyl, C2-C6-Alkenyl,
C2-C6-Alkinyl, C3-C6-Cycloalkyl,
C3-C6-Cycloalkenyl, C6-C14-Aryl, Halogen
und Hydroxyl, und
R3-R10 und
R16-R20 unabhängig voneinander
ausgewählt
aus der Gruppe bestehend aus Wasserstoff, C1-C6-Alkyl, C2-C6-Alkenyl, C2-C6-Alkinyl, C3-C6-Cycloalkyl,
C3-C6-Cycloalkenyl,
C6-C14-Aryl, Amino,
Nitro, Cyano, Formyl, Carboxyl, SO3H, Hydroxy,
Halogen, C1-C4-Halogenalkyl,
C1-C4-Hydroxyalkyl,
C1-C4-Alkylnitril,
C1-C4-Alkoxy, C1-C4-Alkoxy-C1-C4-alkylen, C1-G4-Alkylmercapto, C1-C4-Alkylmercapto-C1-C4-alkylen, C1-C4-Alkoxycarbonyl,
C1-C4-Alkoxycarbonyl-C1-C4-alkylen, Di-C1-C4-alkyl-amino, Di-C1-C4-alkylamino-C1-C4-alkylen, Di-C1-C4-alkylaminocarbonyl
und Di-C1-C4-alkylaminocarbonyl-C1-C4-alkylen.Furthermore, R 1 , R 2 and R 11 -R 15 are preferably selected independently of one another from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 6 -C 14 aryl, halogen and hydroxyl, and
R 3 -R 10 and R 16 -R 20 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 -Cycloalkyl, C 3 -C 6 -cycloalkenyl, C 6 -C 14 -aryl, amino, nitro, cyano, formyl, carboxyl, SO 3 H, hydroxy, halogen, C 1 -C 4 -haloalkyl, C 1 -C 4 -Hydroxyalkyl, C 1 -C 4 alkyl nitrile, C 1 -C 4 alkoxy, C 1 -C 4 alkoxy-C 1 -C 4 alkylene, C 1 -G 4 alkyl mercapto, C 1 -C 4 alkyl mercapto -C 1 -C 4 alkylene, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkoxycarbonyl-C 1 -C 4 alkylene, di-C 1 -C 4 alkylamino, di-C 1 - C 4 -alkylamino-C 1 -C 4 -alkylene, di-C 1 -C 4 -alkylaminocarbonyl and di-C 1 -C 4 -alkylaminocarbonyl-C 1 -C 4 -alkylene.
Besonders bevorzugt sind R1-R6 und R11-R20 in den allgemeinen
Formeln (I), (II) oder (IV) Wasserstoff, und
R7-R10 sind unabhängig voneinander ausgewählt aus
der Gruppe bestehend aus Wasserstoff, C1-C6-Alkyl, C2-C6-Alkenyl, C2-C6-Alkinyl, C3-C6-Cycloalkyl, C3-C6-Cycloalkenyl,
C6-C1
4-Aryl,
Amino, Nitro, Cyano, Formyl, Carboxyl, SO3H,
Hydroxy, Halogen, C1-C4-Halogenalkyl,
C1-C4-Hydroxyalkyl,
C1-C4-Alkylnitril,
C1-C4-Alkoxy, C1-C4-Alkoxy-C1-C4-alkylen, C1-C4-Alkylmercapto, C1-C4-Alkylmercapto-C1-C4-alkylen, C1-C4-Alkoxycarbonyl, C1-C4-Alkoxycarbonyl-C1-C4-alkylen, Di-C1-C4-alkyl-amino, Di-C1-C4-alkylamino-C1-C4-alkylen, Di-C1-C4-alkylaminocarbonyl
und Di-C1-C4-alkylaminocarbonyl-C1-C4-alkylen,
wobei
mindestens einer der Substituenten R7-R10 ungleich Wasserstoff ist.R 1 -R 6 and R 11 -R 20 in the general formulas (I), (II) or (IV) are particularly preferably hydrogen, and
R 7 -R 10 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 6 -C 1 4 -aryl, amino, nitro, cyano, formyl, carboxyl, SO 3 H, hydroxy, halogen, C 1 -C 4 haloalkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkyl nitrile, C 1 -C 4 alkoxy, C 1 -C 4 alkoxy-C 1 -C 4 alkylene, C 1 -C 4 alkyl mercapto, C 1 -C 4 alkyl mercapto-C 1 - C 4 alkylene, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkoxycarbonyl-C 1 -C 4 alkylene, di-C 1 -C 4 alkylamino, di-C 1 -C 4 alkylamino -C 1 -C 4 alkylene, di-C 1 -C 4 alkylaminocarbonyl and di-C 1 -C 4 alkylaminocarbonyl-C 1 -C 4 alkylene,
wherein at least one of the substituents R 7 -R 10 is not hydrogen.
Ganz besonders bevorzugt sind R1-R8 und R10-R20 in den allgemeinen
Formeln (I), (II) oder (IV) Wasserstoff,
und R9 ist
Nitro, Cyano, Halogen oder Trifluormethyl, insbesondere ist R9 eine Nitrogruppe oder ein Halogen, wobei
unter den Halogenen Brom ganz besonders bevorzugt ist.R 1 -R 8 and R 10 -R 20 in the general formulas (I), (II) or (IV) are very particularly preferably hydrogen,
and R 9 is nitro, cyano, halogen or trifluoromethyl, in particular R 9 is a nitro group or a halogen, bromine being very particularly preferred among the halogens.
Weiterhin ist M in den allgemeinen Formeln (III) oder (V) bevorzugt Ga.Furthermore, M is in the general Formulas (III) or (V) preferably Ga.
Insbesondere bevorzugt sind die in den Beispielen gezeigten Verbindungen KP1428, KP1436, KP1437 und KP1438. Die Verbindung KP1428 kann aus der Synthese CH3OH enthalten. Weiterhin können die Verbindungen KP1437 und KP1438 Wasser enthalten.The connections KP1428, KP1436, KP1437 and KP1438 shown in the examples are particularly preferred. The compound KP1428 can contain CH 3 OH from the synthesis. Compounds KP1437 and KP1438 may also contain water.
Organische oder anorganische Additionssalze
können
mit folgenden Anionen gebildet werden:
Chlorid, Bromid, Phosphat,
Carbonat, Nitrat, Perchlorat, Sulfat, Citrat, Lactat, Tartrat, Maleat,
Fumarat, Mandelat, Benzoat, Ascorbat, Cinnamat, Glycollat, Methansulfonat,
Formiat, Malonat, Naphthalin-2-sulfonat, Salicylat und/oder Acetat.Organic or inorganic addition salts can be formed with the following anions:
Chloride, bromide, phosphate, carbonate, nitrate, perchlorate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate, glycolate, methanesulfonate, formate, malonate, naphthalene-2-sulfonate, salicylate and / or Acetate.
Als mögliche Kationen können H+, Natrium- und/oder Kalium-Kationen verwendet werden.H + , sodium and / or potassium cations can be used as possible cations.
Bevorzugt ist Y ausgewählt aus der Gruppe bestehend aus Halogenen, Pseudohalogenen, Nitrat, Carboxylat, Sulfat, Carbonat, Hydrogenphosphat, Tartrat, Malonat, Oxalat und R"COO, wobei R" Wasserstoff, C1-C6-Alkyl, C2-C6-Alkenyl, C2-C6-Alkinyl, C3-C6-Cycloalkyl, C3-C6-Cycloalkenyl, C6-C1 4-Aryl, oder ein Heterocyclus ist .Y is preferably selected from the group consisting of halogens, pseudohalogens, nitrate, carboxylate, sulfate, carbonate, hydrogen phosphate, tartrate, malonate, oxalate and R "COO, where R" is hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 6 -C 1 4 aryl, or a heterocycle.
Besonders bevorzugt ist Y ein Halogen, insbesondere Chlor.Y is particularly preferably a halogen, especially chlorine.
Vorzugsweise ist i 0 oder 1. Bevorzugter ist i 0 oder 1, wenn M Ru oder Fe ist, d.h. in der Oxidationsstufe II bzw. III vorliegt und 1, wenn M Ga ist, d.h. in der Oxidationsstufe III vorliegt.Preferably i is 0 or 1. More preferred i is 0 or 1 if M is Ru or Fe, i.e. in the oxidation state II or III is present and 1 if M is Ga, i.e. in the oxidation state III is present.
Die erfindungsgemäße Verbindung kann zur Prophylaxe und/oder Behandlung von Krebserkrankungen eingesetzt werden.The compound of the invention can be used for prophylaxis and / or treatment of cancer.
Im folgenden wird das Arzneimittel, enthaltend eine erfindungsgemäße Verbindung, genauer beschrieben.The following is the medicine containing a compound according to the invention, described in more detail.
Das erfindungsgemäße Arzneimittel wird vor allem intravenös, aber auch intramuskulär, intraperitoneal, subkutan oder peroral verabreicht. Auch eine äußerliche Applikation ist möglich. Bevorzugt ist die Verabreichung durch intravenöse Injektion oder intravenöse Infusion.The drug according to the invention is mainly intravenously, but also intramuscularly, administered intraperitoneally, subcutaneously or orally. Also an external one Application is possible. Administration by intravenous injection or intravenous infusion is preferred.
Das Arzneimittel wird nach an sich bekannten Verfahren hergestellt, wobei die erfindungsgemäße Verbindung als solche oder gegebenenfalls in Kombination mit geeigneten pharmazeutischen Trägerstoffen eingesetzt wird. Enthält das erfindungsgemäße Arzneimittel neben dem Wirkstoff pharmazeutische Trägerstoffe, beträgt der Wirkstoffgehalt dieser Mischung 0,1 bis 99,5, vorzugsweise 0,5 bis 95 Gew.-% der Gesamtmischung.The medicine is taken by itself known method, the compound of the invention as such or optionally in combination with suitable pharmaceutical excipients is used. contains the medicament according to the invention in addition to the active ingredient pharmaceutical carriers, the active ingredient content is this mixture 0.1 to 99.5, preferably 0.5 to 95 wt .-% of Total mixture.
Das erfindungsgemäße Arzneimittel kann in jeder geeigneten Formulierung angewandt werden unter der Voraussetzung, dass die Ausbildung bzw. Aufrechterhaltung von ausreichenden Wirkstoffpegeln gewährleistet ist. Das kann beispielsweise durch orale oder parenterale Gabe in geeigneten Dosen erreicht werden. Vorteilhafterweise liegt die pharmazeutische Zubereitung des Wirkstoffs in Form von Einheitsdosen vor, die auf die gewünschte Verabreichung abgestimmt sind. Eine Einheitsdosis kann zum Beispiel eine Tablette, ein Dragee, eine Kapsel, ein Suppositorium oder eine gemessene Volumenmenge eines Pulvers, eines Granulates, einer Lösung, einer Emulsion oder einer Suspension sein.The medicament according to the invention can be used in any appropriate wording, provided that the training or maintenance of sufficient drug levels guaranteed is. This can be done, for example, by oral or parenteral administration suitable doses can be achieved. The pharmaceutical is advantageously located Preparation of the active substance in the form of unit doses, based on the desired Administration are coordinated. For example, a unit dose a tablet, dragee, capsule, suppository or measured volume of a powder, a granulate, a solution, one Emulsion or a suspension.
Unter "Einheitsdosis" im Sinne der vorliegenden Erfindung wird eine physikalisch bestimmte Einheit verstanden, die eine individuelle Menge des aktiven Bestandteils in Kombination mit einem pharmazeutischen Trägerstoff enthält und deren Wirkstoffgehalt einem Bruchteil oder Vielfachen einer therapeutischen Einzeldosis entspricht. Eine Einzeldosis enthält vorzugsweise die Menge Wirkstoff, die bei einer Applikation verabreicht wird und die gewöhnlich einer ganzen, einer halben, einer drittel oder einer viertel Tagesdosis entspricht. Wenn für eine einzelne therapeutische Verabreichung nur ein Bruchteil, wie die Hälfte oder ein Viertel der Einheitsdosis benötigt wird, ist die Einheitsdosis vorteilhafterweise teilbar, z.B. in Form einer Tablette mit Bruchkerbe.Under "unit dose" in the sense of the present invention is understood to be a physically determined unit that is an individual Amount of active ingredient in combination with a pharmaceutical carrier contains and their active ingredient content a fraction or multiples of one corresponds to a single therapeutic dose. A single dose preferably contains the amount of active ingredient that is administered in one application and usually a whole, a half, a third or a quarter of a daily dose equivalent. If for a single therapeutic administration just a fraction, like the half or a quarter of the unit dose is needed is the unit dose advantageously divisible, e.g. in the form of a tablet with a score line.
Die erfindungsgemäßen Arzneimittel können, wenn sie in Einheitsdosen vorliegen und für Applikationen z.B. am Menschen bestimmt sind, etwa 0,1 bis 500 mg, bevorzugt 10 bis 200 mg und insbesondere 50 bis 150 mg Wirkstoff enthalten.The medicaments according to the invention can if they are available in unit doses and for applications e.g. on people are determined, about 0.1 to 500 mg, preferably 10 to 200 mg and contain in particular 50 to 150 mg of active ingredient.
Im allgemeinen werden in der Humanmedizin der oder die Wirkstoffe in einer Tagesdosis von 0,1 bis 5, vorzugsweise 1 bis 3 mg/kg Körpergewicht, gegebenenfalls in Form mehrerer, vorzugsweise 1 bis 3 Einzelgaben zur Erzielung der gewünschten Ergebnisse verabreicht. Eine Einzelgabe enthält den oder die Wirkstoffe in Mengen von 0,1 bis 5, vorzugsweise 1 bis 3 mg/kg Körpergewicht. Bei einer oralen Behandlung können ähnliche Dosierungen zur Anwendung kommen.In general, in human medicine the active ingredient (s) are administered in a daily dose of 0.1 to 5, preferably 1 to 3 mg / kg body weight, optionally in the form of several, preferably 1 to 3, single doses to achieve the desired results. A single dose contains the active ingredient (s) in amounts of 0.1 to 5, preferably 1 to 3 mg / kg body weight. Oral treatment can be similar doses are used.
Die therapeutische Verabreichung des erfindungsgemäßen Arzneimittels kann 1 bis 4 mal am Tage zu festgelegten oder variierenden Zeitpunkten erfolgen, z.B. jeweils vor den Mahlzeiten und/oder am Abend. Es kann jedoch erforderlich sein, von den genannten Dosierungen abzuweichen, und zwar in Abhängigkeit von der Art, dem Körpergewicht und dem Alter der zu behandelnden Individuen, der Art und Schwere der Erkrankung, der Art der Zubereitung und der Applikation des Arzneimittels sowie dem Zeitraum bzw. Intervall, innerhalb welchem die Verabreichung erfolgt. So kann es in einigen Fällen ausreichend sein, mit weniger als der oben genannten Menge Wirkstoff auszukommen, während in anderen Fällen die oben angeführte Wirkstoffmenge überschritten werden muss. Es kann sich auch als zweckmäßig erweisen, die Arzneimittel nur einmalig oder im Abstand von mehreren Tagen zu verabreichen.The therapeutic administration of the medicament according to the invention can be 1 to 4 times a day at fixed or varying times take place, e.g. before meals and / or in the evening. It can however, it may be necessary to deviate from the doses mentioned, depending on it on the type, the body weight and the age of the individuals to be treated, the type and severity the disease, the type of preparation and the application of the Drug and the period or interval within which the administration takes place. So in some cases it may be sufficient be able to make do with less than the above-mentioned amount of active ingredient, while in other cases the above Active substance amount exceeded must become. It may also prove useful to take the medication to be administered only once or at intervals of several days.
Die Festlegung der erforderlichen optimalen Dosierung und Applikationsart der Wirkstoffe kann durch jeden Fachmann aufgrund seines Fachwissens erfolgen.The determination of the required Optimal dosage and type of application of the active ingredients can be determined by everyone Specialist based on his specialist knowledge.
Die erfindungsgemäßen Arzneimittel bestehen in der Regel aus den erfindungsgemäßen Verbindungen und nichttoxischen, pharmazeutisch verträglichen Arzneimittelträgern, die als Zumischung oder Verdünnungsmittel, beispielsweise in fester, halbfester oder flüssiger Form oder als Umhüllungsmittel, beispielsweise in Form einer Kapsel, eines Tablettenüberzugs, eines Beutels oder eines anderen Behältnisses für den therapeutisch aktiven Bestandteil in Anwendung kommen. Ein Trägerstoff kann z.B. als Vermittler für die Arzneimittelaufnahme durch den Körper, als Formulierungshilfsmittel, als Süßungsmittel, als Geschmackskorrigens, als Farbstoff oder als Konservierungsmittel dienen.The medicaments according to the invention consist of usually from the compounds of the invention and non-toxic, pharmaceutically acceptable drug carriers that as an admixture or diluent, for example in solid, semi-solid or liquid form or as a coating agent, for example in the form of a capsule, a tablet coating, a bag or other container for the therapeutically active Component. A carrier can e.g. as an intermediary for the Drug absorption by the body, as a formulation aid, as a sweetener, as a taste corrector, serve as a dye or as a preservative.
Zur oralen Anwendung können z.B. Tabletten Dragees, harte und weiche Kapseln, z.B. aus Gelatine, dispergierbare Pulver, Granulate, wässrige und ölige Suspensionen, Emulsionen, Lösungen oder Sirupe kommen.For oral use e.g. Tablets dragees, hard and soft capsules, e.g. made of gelatin, dispersible Powder, granules, aqueous and oily Suspensions, emulsions, solutions or syrups are coming.
Tabletten können inerte Verdünnungsmittel, z.B. Calciumcarbonat, Calciumphosphat, Natriumphosphat oder Laktose; Granulierungs- und Verteilungsmittel, z.B. Maisstärke oder Alginate; Bindemittel, z.B. Stärke, Gelatine oder Akaziengummi; und Gleitmittel, z.B. Aluminium- oder Magnesiumstearat, Talkum oder Silikonöl, enthalten. Sie können zusätzlich mit einem Überzug versehen sein, der auch so beschalten sein kann, dass er eine verzögerte Auflösung und Resorption der Arzneimittelzubereitung im Gastrointestinaltrakt bewirkt, so dass z.B. eine bessere Verträglichkeit, Protahierung oder Retardierung erreicht wird. Gelatinekapseln können den Arzneistoff vermischt mit einem festen, z.B. Calciumcarbonat oder Kaolin, oder einem öligen, z.B. Oliven-, Erdnuss-, oder Paraffinöl, Verdünnungsmittel enthalten.Tablets can contain inert diluents, e.g. Calcium carbonate, calcium phosphate, sodium phosphate or lactose; Granulating and distributing agents, e.g. Cornstarch or alginates; Binders, e.g. Strength, Gelatin or acacia; and lubricants, e.g. Aluminum or Magnesium stearate, talc or silicone oil. You can also use a coating be provided, which can also be wired so that it has a delayed resolution and Absorption of the drug preparation in the gastrointestinal tract causes so that e.g. better tolerance, contracting or Retardation is achieved. Gelatin capsules can mix the drug with a fixed, e.g. Calcium carbonate or kaolin, or an oily, e.g. Olive, peanut or paraffin oil, thinner contain.
Wässrige Suspensionen können Suspendiermittel, z.B. Natriumcarboxymethylcellulose, Methylcellulose, Hydroxypropylcellulose, Natriumalginat, Polyvinylpyrrolidon, Traganthgummi oder Akaziengummi; Dispergier- und Benetzungsmittel, z.B. Polyoxyethylenstearat, Heptadecaethylenoxycatanol, Polyoxyethylensorbitolmonooleat oder Lecithin; Konservierungsmittel, z.B. Methyl- oder Propylhydroxybenzoate; Geschmacksmittel; Süßungsmittel, z.B. Saccharose, Lactose, Natriumcyclamat, Dextrose, Invertzuckersirup, enthalten.aqueous Suspensions can Suspending agents, e.g. Sodium carboxymethyl cellulose, methyl cellulose, Hydroxypropyl cellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth or acacia; Dispersing and wetting agents, e.g. polyoxyethylene stearate, Heptadecaethyleneoxycatanol, polyoxyethylene sorbitol monooleate or lecithin; Preservatives, e.g. Methyl or propyl hydroxybenzoates; Flavoring agents; sweeteners e.g. Sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup, contain.
Ölige Suspensionen können z.B. Erdnuss-, Oliven-, Sesam-, Kokos- oder Paraffinöl und Verdickungsmittel, wie z.B. Bienenwachs, Hartparaffin oder Cetylalkohol, enthalten; ferner Süßungsmittel, Geschmacksmittel und Antioxidantien.oily Suspensions can e.g. Peanut, olive, sesame, coconut or paraffin oil and thickeners, such as. Beeswax, hard paraffin or cetyl alcohol; also sweeteners, Flavorings and antioxidants.
In Wasser dispergierbare Pulver und Granulate können die erfindungsgemäße Verbindung in Mischung mit Dispergier-; Benetzungs- und Suspendiermitteln, z.B. den oben genannten, sowie mit Süßungsmitteln, Geschmacksmitteln und Farbstoffen enthalten.Water dispersible powders and Granules can the compound of the invention in mixture with dispersing; Wetting and suspending agents, e.g. the above, as well as with sweeteners, flavoring agents and dyes included.
Emulsionen können z.B. Oliven-, Erdnuss-, oder Paraffinöl neben Emulgiermitteln, wie z.B. Akaziengummi, Traganthgummi, Phosphatiden, Sorbitanmonooleat, Polyoxyethylensorbitanmonooleat, und Süßungs- und Geschmacksmittel enthalten.Emulsions can e.g. Olive, peanut, or paraffin oil in addition to emulsifiers, e.g. Acacia, tragacanth, phosphatides, Sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweetening and flavoring agents contain.
Wässrige Lösungen können Konservierungsmittel, z.B. Methyl- oder Propylhydroxybenzoate; Verdickungsmittel; Geschmacksmittel; Süßungsmittel, z.B. Saccharose, Laktose, Natriumcyclamat, Dextrose, Invertzuckersirup, sowie Geschmacksmittel und Farbstoffe enthalten.aqueous solutions can Preservatives, e.g. Methyl or propyl hydroxybenzoates; Thickener; Flavoring agents; sweeteners e.g. Sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup, as well as flavoring and coloring agents.
Zur parenteralen Anwendung der Arzneistoffe dienen steril injizierbare, wässrige Lösungen, isotonische Salzlösungen oder sonstige Lösungen.For parenteral use of the drugs are used for sterile injectable, aqueous Solutions, isotonic saline solutions or other solutions.
Die folgenden Beispiele erläutern die Erfindung.The following examples illustrate the Invention.
Reaktion von Anthranilsäureethylester mit Bernsteinsäureethylester (1) (JACS, 1958, 80. 2172): Reaction of ethyl anthranilate with ethyl succinate (1) (JACS, 1958, 80, 2172):
Eine Mischung bestehend aus 14.7 g Bernsteinsäureethylester, 10.3 g Anthranilsäureethylester, und 2.14 g Natriumhydrid wurde in 140 mL trockenem Toluol 3 Stunden unter Rühren zum Rückfluss erhitzt. Die Reaktionsmischung wurde über Nacht stehen gelassen, und anschließend wurden 75 mL 10%ige Salzsäure langsam zugegeben. Der sich bildende Niederschlag wurde abfiltriert und dreimal aus Ethanol umkristallisiert. Ausbeute: 4.5 g (29.5%), Smp.: 210-213°C; IR: 1673 cm–1 (Konjugierter Ester), 1648 cm–1 (Amid), 1623 cm–1 (C=C); λmax(Ethanol) 228–229 nm (ε = 29260), 239 nm (ε = 19580) sh, 293–296 nm (ε = 12200). Anal. Ber. für C1 2H13NO4 (235.24): C, 63.15; H, 5.30; N, 5.67. Gef.: C, 63.31; H, 5.45; N, 5.78.A mixture consisting of 14.7 g of ethyl succinate, 10.3 g of ethyl anthranilate and 2.14 g of sodium hydride was heated to reflux in 140 ml of dry toluene with stirring for 3 hours. The reaction mixture was left to stand overnight, and then 75 mL of 10% hydrochloric acid was slowly added. The precipitate that formed was filtered off and recrystallized three times from ethanol. Yield: 4.5 g (29.5%), m.p .: 210-213 ° C; IR: 1673 cm -1 (conjugated ester), 1648 cm -1 (amide), 1623 cm -1 (C = C); λ max (ethanol) 228-229 nm (ε = 29260), 239 nm (ε = 19580) sh, 293-296 nm (ε = 12200). Anal. Ber. for C 1 2 H 13 NO 4 (235.24): C, 63.15; H, 5.30; N, 5.67. Found: C, 63.31; H, 5.45; N, 5.78.
2,3,4,5-Tetrahydro-1H-1-benzazepin-2,5-dion (Arch. Pharm. 1991, 324, 579): 2,3,4,5-tetrahydro-1H-1-benzazepine-2,5-dione (Arch. Pharm. 1991, 324, 579):
494 mg (2 mmol) 1 wurden mit 0.07 ml (3.9 mmol) Wasser in 10 ml DMSO unter Rühren unter N2 auf 150°C erhitzt. Nach 1 h wurde in 50 ml Wasser gegossen und 10 mal mit je 10 ml CH2Cl2 extrahiert. Die vereinigten org. Phasen wurden mit Wasser gewaschen, über Na2SO4 getrocknet und i. Vak. eingedampft. Umkristallisation des Rückstands aus Ethanol ergab farblose Kristalle. Ausbeute 85%, Smp.: 187–188°C (EtOH). C10H9NO (175.2); IR: 3220 (NH), 1660 cm–1 (C=O); 1H NMR (DMSO-d6) δ(ppm): 10.05 (bs; 1H, NH), 7.81 (dd; 1H, J = 1.5/8 Hz, Haromat), 7.53 (ddd; 1H, J = 1.5/7/8 Hz, Naromat), 7.19–7.13 (m; 2Haromat), 2.63–2.93 (m, AA'BB'; 4H, CH2CH2). EI MS: m/z(%) = 175 (93%, M+).494 mg (2 mmol) 1 were heated to 150 ° C. with 0.07 ml (3.9 mmol) water in 10 ml DMSO while stirring under N 2 . After 1 h, the mixture was poured into 50 ml of water and extracted 10 times with 10 ml of CH 2 Cl 2 each. The united org. Phases were washed with water, dried over Na 2 SO 4 and i. Vak. evaporated. Recrystallization of the residue from ethanol gave colorless crystals. Yield 85%, m.p .: 187-188 ° C (EtOH). C 10 H 9 NO (175.2); IR: 3220 (NH), 1660 cm- 1 (C = O); 1 H NMR (DMSO-d 6 ) δ (ppm): 10.05 (bs; 1H, NH), 7.81 (dd; 1H, J = 1.5 / 8 Hz, H aromat ), 7.53 (ddd; 1H, J = 1.5 / 7/8 Hz, N aromat ), 7.19-7.13 (m; 2H aromat ), 2.63-2.93 (m, AA'BB '; 4H, CH 2 CH 2 ). EI MS: m / z (%) = 175 (93%, M + ).
9-Brom-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-on(3) (Arch. Pharm. 1992, 325, 297): 9-bromo-7,12-dihydro-indolo [3,2-d] [1] benzazepin-6 (5H) -one (3) (Arch. Pharm. 1992, 325, 297):
Zu einer Suspension von 2 (1.05 g, 6 mmol) in Eisessig (10 ml) wurde Bromphenylhydrazin (7 mmol) zugegeben, anschließend wurde 1 h bei 70°C gerührt. Nach dem Abkühlen wurde mit 0.5 ml konz. H2SO4 1 h bei 70°C gerührt. Man ließ abkühlen, goß in 50 ml 10 proz. Natriumacetatlösung und saugte den Niederschlag ab. Gelbe Kristalle. Ausbeute: 58%. Smp.: > 330°C (1,4-Dioxan). C16H11BrN2O (327.2). IR: 3220 (NH); 1640 cm–1 (C=O).1H NMR: δ (ppm): 11.75 (s; 1H, NH), 10.05 (s; 1H, NH), 7.89 (d; 1H, J = 1.5 Hz, C-8-H), 7.74 (bd; 1H, J = 7.5 Hz, Ar-H), 7.41–7.34 (m; 2H, Ar-H), 7.30–7.21 (m; 3H, Ar-H), 3.50 (s; 2H, CH2).Bromophenylhydrazine (7 mmol) was added to a suspension of 2 (1.05 g, 6 mmol) in glacial acetic acid (10 ml), followed by stirring at 70 ° C. for 1 h. After cooling, 0.5 ml of conc. H 2 SO 4 stirred at 70 ° C for 1 h. The mixture was allowed to cool, poured into 50 ml of 10 percent. Sodium acetate solution and sucked the precipitate from. Yellow crystals. Yield: 58%. M.p .:> 330 ° C (1,4-dioxane). C 16 H 11 BrN 2 O (327.2). IR: 3220 (NH); 1640 cm -1 (C = O). 1 H NMR: δ (ppm): 11.75 (s; 1H, NH), 10.05 (s; 1H, NH), 7.89 (d; 1H, J = 1.5 Hz, C-8-H), 7.74 (bd; 1H , J = 7.5 Hz, Ar-H), 7.41-7.34 (m; 2H, Ar-H), 7.30-7.21 (m; 3H, Ar-H), 3.50 (s; 2H, CH 2 ).
9-Bromo-7,12-dihydroindolo[3,2-d][1]benzazepine-6-(5M)-thion (4) J. Med. Chem. 1999, 42, 2909): 9-Bromo-7,12-dihydroindolo [3,2-d] [1] benzazepine-6- (5M) -thione (4) J. Med. Chem. 1999, 42, 2909):
Eine Lösung von 3 (327 mg, 1 mmol) in THF (30 mL) wurde bei 50°C unter einer Stickstoffschutzgasatmosphäre gerührt. Nacheinander wurden Phosphorpentasulfid (250 mg, 1.12 mmol) und Natriumhydrogencarbonat (370 mg, 4.4 mmol) zugegeben. Nachdem 3 Stunden unter Rückfluss in einer Stickstoffschutzgasatmosphäre erhitzt worden war, ließ man die Reaktionsmischung auf Raumtemperatur abkühlen und überführte die Reaktionsmischung danach auf Eis (50 g). Bis zum vollständigen Schmelzen des Eises wurde gerührt, der sich bildende Niederschlag wurde abgesaugt, mit Wasser gewaschen und aus Ethanol/Toluol umkristallisiert. Ausbeute: 67% schwach-gelbe Kristalle: Smp.: > 330°C; IR: 3430, 3140 cm–1 (NH); 1H NMR (400 MHz) 3.91 (s, 2H, CH2), 7.30 (dd, 1H, 1.5/8.6 Hz), 7.39–7.45 (m, 4H), 7.79 (d, 1H, 7.1 Hz), 7.86 (d, 1H, 1.5 Hz), 11.92 (s, 1H, NH), 12.07 (s, 1H, NH).A solution of 3 (327 mg, 1 mmol) in THF (30 mL) was stirred at 50 ° C under a protective nitrogen atmosphere. Phosphorus pentasulfide (250 mg, 1.12 mmol) and sodium hydrogen carbonate (370 mg, 4.4 mmol) were added in succession. After heating under reflux in a nitrogen blanket for 3 hours, the reaction mixture was allowed to cool to room temperature and then transferred to ice (50 g). The mixture was stirred until the ice had completely melted, and the precipitate which formed was filtered off with suction, washed with water and recrystallized from ethanol / toluene. Yield: 67% pale yellow crystals: mp:> 330 ° C; IR: 3430, 3140 cm -1 (NH); 1 H NMR (400 MHz) 3.91 (s, 2H, CH 2 ), 7.30 (dd, 1H, 1.5 / 8.6 Hz), 7.39-7.45 (m, 4H), 7.79 (d, 1H, 7.1 Hz), 7.86 ( d, 1H, 1.5 Hz), 11.92 (s, 1H, NH), 12.07 (s, 1H, NH).
9-Bromo-6-(methylthio)-7,12-dihydroindolo[3,2-d][1]-benzazepin (5) J. Med. Chem. 1999, 42, 2909): 9-Bromo-6- (methylthio) -7,12-dihydroindolo [3,2-d] [1] -benzazepine (5) J. Med. Chem. 1999, 42, 2909):
Zu einer Lösung von 4 (343 mg, 1 mmol) in THF (20 mL) wurde Natriumhydrid (24 mg, 1 mmol, 60%ige Suspension in Öl) zugegeben. Nachdem 1 Stunde unter Rühren in einer Stickstoffschutzgasatmosphäre zum Rückfluss erhitzt worden war, wurde die Mischung auf Raumtemperatur abgekühlt und eine Lösung von Iodmethan (170 mg, 1.2 mmol) in THF (2 mL) zugegeben. Es wurde weitere 2 Stunden unter Rückfluss erhitzt, erneut auf Raumtemperatur abgekühlt, und danach wurde das Reaktionsgemisch auf Eis (150 mL) überführt. Nach 15 minütigem Rühren wurde der Niederschlag abgesaugt, mit Wasser gewaschen und aus Ethanol kristallisiert. Ausbeute: 44% farblose Kristalle; Smp.: 199°C; IR: 3420 (NH), 1615 cm–1 (C=N); 1H NMR (400 MHz) 2.35 (s, 3H, CH3), 3.51 (s, 2H, CH2), 7.26–7.32 (m, 2H), 7.36–7.43 (m, 3H), 7.80-7.82 (m, 1H), 7.97 (d, 1H, 1.5 Hz), 11.82 (s, 1H, NH).Sodium hydride (24 mg, 1 mmol, 60% suspension in oil) was added to a solution of 4 (343 mg, 1 mmol) in THF (20 mL). After heating to reflux for 1 hour with stirring in a nitrogen blanket, the mixture was cooled to room temperature and a solution of iodomethane (170 mg, 1.2 mmol) in THF (2 mL) was added. The mixture was heated under reflux for a further 2 hours, cooled again to room temperature, and then the reaction mixture was transferred to ice (150 ml). After stirring for 15 minutes, the precipitate was filtered off, washed with water and crystallized from ethanol. Yield: 44% colorless crystals; M.p .: 199 ° C; IR: 3420 (NH), 1615 cm -1 (C = N); 1 H NMR (400 MHz) 2.35 (s, 3H, CH 3 ), 3.51 (s, 2H, CH 2 ), 7.26-7.32 (m, 2H), 7.36-7.43 (m, 3H), 7.80-7.82 (m , 1H), 7.97 (d, 1H, 1.5 Hz), 11.82 (s, 1H, NH).
KP1428: KP1428:
Zu 5 (714 mg, 2 mmol) in Methanol (35 mL) wurde Thiosemicarbazid (220 mg) in Methanol ( 55 mL) zugegeben. Die Lösung wurde filtriert und bei Raumtemperatur gelagert. Nach 4 Tagen wurde der gebildete Niederschlag abfiltriert, mit Methanol gewaschen und an der Luft getrocknet. Ausbeute: 490 mg. Ber. Für C18H18N5BrOS, %: C, 50.01; H, 4.20; H, 16.20. Gef., %: C, 50.12, H, 4.55; H, 15.63. MS (ESI): m/z = 400 [M+].To 5 (714 mg, 2 mmol) in methanol (35 mL) was added thiosemicarbazide (220 mg) in methanol (55 mL). The solution was filtered and stored at room temperature. After 4 days, the precipitate formed was filtered off, washed with methanol and air-dried. Yield: 490 mg. Ber. For C 18 H 18 N 5 BrOS,%: C, 50.01; H, 4.20; H, 16.20. Found,%: C, 50.12, H, 4.55; H, 15.63. MS (ESI): m / z = 400 [M + ].
KP1436: KP1436:
Zu 5 (714 mg, 2 mmol) in trockenem Ethanol (50 mL) wurde Hydrazin-Hydrat (0.2 mL) gegeben. Die Lösung wurde filtriert und danach bei Raumtemperatur gelagert. Nach 2 Tagen wurde der gebildete Niederschlag abfiltriert, mit Ethanol gewaschen und an der Luft getrocknet. Ausbeute: 236 mg. Ber. für C1 6H1 3N4Br, %: C, 56.32; H, 3.84; N, 16.42. Gef., %: C, 56.19, H, 3.80; N, 16.22. MS (ESI): m/z = 341 [M+].Hydrazine hydrate (0.2 mL) was added to 5 (714 mg, 2 mmol) in dry ethanol (50 mL). The solution was filtered and then stored at room temperature. After 2 days, the precipitate formed was filtered off, washed with ethanol and air-dried. Yield: 236 mg. Ber. for C 1 6 H 1 3 N 4 Br,%: C, 56.32; H, 3.84; N, 16.42. Found,%: C, 56.19, H, 3.80; N, 16.22. MS (ESI): m / z = 341 [M + ].
KP1437: KP1437:
Zu KP1436 in siedendem Methanol (30 mL) wurde 2-Hydroxybenzaldehyd zugegeben, und die Lösung wurde erwärmt bis alles Ausgangsmaterial gelöst war. Am nächsten Tag wurde der Niederschlag abfiltriert, mit Methanol gewaschen und an der Luft getrocknet. Ausbeute: 150 mg. Ber. für C23H1 9N4O2Br, %: C, 59.62; H, 4.13; N, 12.09. Gef.: %: C, 60.23, H, 4.17; N, 12.12. MS (ESI): m/z = 445 [M+].2-Hydroxybenzaldehyde was added to KP1436 in boiling methanol (30 mL) and the solution was warmed until all of the starting material was dissolved. The next day the precipitate was filtered off, washed with methanol and air dried. Yield: 150 mg. Ber. for C 23 H 1 9 N 4 O 2 Br,%: C, 59.62; H, 4.13; N, 09/12. Found:%: C, 60.23, H, 4.17; N, 12/12 MS (ESI): m / z = 445 [M + ].
KP1438: KP1438:
KP1436 (170 mg, 4.9 mmol) wurde in Methanol (30 mL) zum Sieden erhitzt und 2-Hydroxybenzaldehyd (60 mg, 4.9 mmol) in Methanol (1 mL) wurde zugegeben. Das Reaktionsgemisch wurde 15 min unter Rückfluss erhitzt. Nachdem das Edukt vollständig in Lösung gegangen war, begann KP1437 auszukristallisieren. An diesem Punkt wurde eine Lösung aus GaCl3 (2.45 mmol) in Ethanol (0.3 mL) zugegeben. Die so erhaltene Lösung wurde 20 min zum Rückfluss erhitzt und danach bei Raumtemperatur stehen gelassen. Am nächsten Tag wurde der Niederschlag abfiltriert, mit kaltem Methanol gewaschen und im Vakuum getrocknet. Ausbeute: 90 mg. Die Ausbeute kann auf 140 mg verbessert werden, wenn die Reaktion in Gegenwart von 0.05 g Triethylamin durchgeführt wird. Ber. für C46H32N8GaBr2ClO22.5H2O, %: C, 53.19; H, 3.59; N, 10.79. Gef., %: C, 52.89, H, 3.60; N, 10.63. MS (ESI): m/z = 957 [M+–Cl].KP1436 (170 mg, 4.9 mmol) was heated to boiling in methanol (30 mL) and 2-hydroxybenzaldehyde (60 mg, 4.9 mmol) in methanol (1 mL) was added. The reaction mixture was refluxed for 15 minutes. After the starting material had completely dissolved, KP1437 began to crystallize out. At this point a solution of GaCl 3 (2.45 mmol) in ethanol (0.3 mL) was added. The solution thus obtained was heated to reflux for 20 minutes and then left to stand at room temperature. The next day the precipitate was filtered off, washed with cold methanol and dried in vacuo. Yield: 90 mg. The yield can be improved to 140 mg if the reaction is carried out in the presence of 0.05 g of triethylamine. Ber. for C 46 H 32 N 8 GaBr 2 ClO 2 2.5H 2 O,%: C, 53.19; H, 3.59; N, 10.79. Found,%: C, 52.89, H, 3.60; N, 10.63. MS (ESI): m / z = 957 [M + - Cl].
Tumorhemmende Wirkung:Anti-tumor effect:
Die tumorhemmende Wirkung wurde im XTT-Assay am Beispiel verschiedener Zellinien in-vitro getestet. Die Inkubationszeit betrug 48 Stunden (lC50-Werte in μM). The tumor-inhibiting effect was tested in the XTT assay using the example of various cell lines in vitro. The incubation period was 48 hours (IC 50 values in μM).
Claims (15)
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PCT/EP2003/014831 WO2004058766A2 (en) | 2002-12-23 | 2003-12-23 | Tumour-inhibiting annellated azepinone derivatives |
EP03767828A EP1581534A2 (en) | 2002-12-23 | 2003-12-23 | Tumour-inhibiting annellated azepinone derivatives |
CA002551576A CA2551576A1 (en) | 2002-12-23 | 2003-12-23 | Tumour-inhibiting annellated azepinone derivatives |
JP2004563198A JP2006515591A (en) | 2002-12-23 | 2003-12-23 | Cyclic azepinone derivatives that inhibit tumors |
AU2003292264A AU2003292264A1 (en) | 2002-12-23 | 2003-12-23 | Tumour-inhibiting annellated azepinone derivatives |
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WO1999065910A1 (en) * | 1998-06-16 | 1999-12-23 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Fused azepinone cyclin dependent kinase inhibitors |
WO2001060374A1 (en) * | 2000-02-15 | 2001-08-23 | Centre National De La Recherche Scientifique (C.N.R.S.) | Use of paullone derivatives for making medicines |
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WO1999065910A1 (en) * | 1998-06-16 | 1999-12-23 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Fused azepinone cyclin dependent kinase inhibitors |
WO2001060374A1 (en) * | 2000-02-15 | 2001-08-23 | Centre National De La Recherche Scientifique (C.N.R.S.) | Use of paullone derivatives for making medicines |
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